Type 1 diabetes (T1D), which results from autoimmunity directed against insulin-producing islet cells, has devastating effects on health and quality of life. In this application we propose to investigate the role of an important new subpopulation of CD8 T cells in new-onset diabetes patients. This population is defined by expression of the IL-18 receptor (IL-18R) and contains cells with both innate and effector features. The goal of this application is to understand the role of this IL-18R-positive CD8 T cell subpopulation in human T1D. This work is important for several reasons. First, this expanded and unique T cell subpopulation has never been described in circulating leukocytes of new-onset human Type 1 diabetics. Second, IL-18 and its receptor are risk factors for autoimmune diseases, indicating that these factors may induce autoimmune reactions related to type 1 diabetes. Third, the IL-18 binding protein has been evaluated for its use in clinical trials for rheumatoid arthritis, and the work described here could provide the basis for clinical trials with the binding protein in diabetes patients. Fourth, the presence of this specific cell population could be developed as a surrogate marker for disease susceptibility and identify patients who would respond positively to treatment with the binding protein. Fifth, our results will provide critical proof of concept data on the activation and pathogenicity of this cell population in human diabetes. Sixth, these investigations will uncover the role of circulating factors that stimulate or inhibit the pathogenic potential of this cell population. Therefore, our approach will provide novel findings facilitating clinical trials blocking the IL-18R pathway in new-onset diabetes patients. PUBLIC HEALTH RELEVANCE: Type1 diabetes has devastating effects on the health and quality of life of those affected. We have recently obtained data suggesting that an immune cell population expressing the interleukin 18 receptor (IL-18R) is important in precipitating the onset of autoimmune diabetes. The work proposed in the application will test the role of the IL-18R expressing cells in this disease and will provide a new model for understanding the mechanism of diabetes development in humans. This work will open new avenues for the prevention and treatment of human type 1 diabetes.